The invention relates to tissue and organ transplantation.
The major limitation to long-term survival after organ transplantation in humans is the development of chronic rejection. Cardiac transplantation, for example, is frequently characterized by an obliterative arteriosclerosis with progressive thickening of the interior of the blood vessel that eventually results in ischemic injury (Schoen, F. J. and P. Libby, 1991, Cardiac Transplant Graft Arteriosclerosis, Trends Cardiovasc. Med., 1:216-223; Sharples, L. D., N. Caine, P. Mullins, J. P. Scott, E. Solis, T. A. English, S. R. Large, P. M. Schofield, and J. Wallwork, 1991, Risk factor analysis for the major hazards following heart transplantation-rejection, infection, and coronary occlusive disease, Transplantation, 52:244-252; Cramer, D. V., 1993, Graft Arteriosclerosis in Heart Transplantation, R. G. Landes Company, Austin, Tex.). Studies of vessels from human heart transplant recipients have revealed an intimal hyperplasia that is concentric and diffuse, involves a spectrum of vessels, and is highly prevalent. In the first stage of arteriosclerotic thickening, monocytes/macrophages accumulate. In the intermediate stage, macrophages and smooth muscle cells both accumulate, and in the later more obliterative stage, smooth muscle cells predominate.
Chronic transplant rejection is likely to be a complex process mediated by a spectrum of factors which have been difficult to eliminate. Transplant arteriosclerosis occurs only in the donor heart and spares the host vessels. One hypothesis about the arteriosclerotic process holds that a chronic, cell-mediated immune response to alloantigens produces cytokines that mediate neointimal smooth muscle cell accumulation in the graft-derived vasculature, in a manner analogous to the process of delayed-type hypersensitivity (Schoen et al., supra), but little is known about factors that regulate the specific localization or function of mononuclear cells in the interstitium and vessels of cardiac allografts. The pathogenesis of transplant arteriosclerosis is unknown, and studies to elucidate the process have been limited by difficulty in obtaining useful clinical specimens.